Project Summary Abstract Prostate cancer (PCa) and Alzheimer's disease (AD) have several similarities including increasing age as a major risk factor, higher frequency of apolipoprotein E ? allele in both, etc. Several population based studies have confirmed a close association between PCa and AD, where PCa patients are at a higher risk for AD development; and AD patients have higher possibility of developing PCa. Few studies have also reported the direct effect of gonadal hormones on amyloid-? (A?) peptide. Consequently, anti-androgen therapy in PCa patients increases plasma A? levels, and significantly increases the risk for dementia associated with AD and vascular cognitive impairment. Overall, PCa and AD seem to share similar pathogenesis pattern. In the funded R01 application, we have propounded that social stress factors such as neighborhood environment, violence, racial segregation, and social isolation are associated with dysregulated hypothalamic?pituitary?adrenal axis and the resultant biological stressors such as cortisol and leptin could alter the epigenome. Consequentially, PCa patients living in such adverse social environment are likely to experience different and highly complex biological manifestations due to such social-stress-modulated epigenetic response. We believe these socio- epigenome factors could be the one reason for PCa aggressiveness in African-Americans, a race that faces a serious PCa-related health disparity. Our goal in the funded R01 is to identify the role of miRNAs and stress hormones in prostate carcinogenesis in African Americans. Interestingly, higher cortisol levels are also associated with AD development. Based upon the strong association between PCa and AD, and the availability of serum samples from African American men (healthy and PCa) with distinct social backgrounds in the funded R01, in this application, we propose to assess whether social factors such as socio-economic status and differential stress hormone levels promote the AD risk in African American PCa patients. Following are the specific aims: (A) To characterize neuron-derived exosomes (NDE) and astrocyte-derived exosomes (ADE) from participants for AD-related biomarkers. We will isolate L1CAM+ NDE and GLAST+ ADE from the serum of 50 African Americans (healthy (n=25) and PCa (n=25) patients) and analyze for A?1-42 and tau (P-T181-tau, P-S396-tau and total tau) levels by ELISA, and correlate their expression with cortisol and leptin levels in the blood. Further, exosomes will be analyzed for their cargo (miRNAs and proteins) to assess expression of biomarkers associated with dementia (AD and vascular cognitive impairment). (B) To determine how NDE and ADE from participants affect synaptic function. Effect of exosomes (NDE and ADE) treatment will be analyzed on synaptic plasticity via assessing hippocampal long-term potentiation (LTP), a cellular model for memory. Further, hippocampal slices will be analyzed for synaptic biomarkers known to be dysregulated in AD and vascular cognitive impairment. Overall, outcomes of these studies will elucidate the effect of social stressors and stress hormones on AD-related biomarkers in African American men with PCa.